THE PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR-γ LIGAND 15-DEOXYD12,14 PROSTAGLANDIN J2 REDUCES THE ORGAN INJURY IN HEMORRHAGIC SHOCK

Abstract

The cyclopentenone prostaglandin 15-deoxyDelta12,14PGJ2 (15d-PGJ2) exerts potent anti-inflammatory effects in vivo, which are in part caused by the activation of peroxisome proliferator-activated receptor-gamma (PPAR-gamma). Here we investigate the effects of 15d-PGJ2 on the multiple organ injury/dysfunction associated with severe hemorrhage and resuscitation. Male Wistar rats were subjected to hemorrhage (to lower mean arterial blood pressure to 45 mmHg) for 90 min and subsequently resuscitated with shed blood for 4 h. Rats were treated with either 15d-PGJ2 (0.3 mg/kg i.v.) or its vehicle (10% dimethyl sulfoxide) at 30 min before the hemorrhage. In some experiments, the selective PPAR-gamma antagonist GW9662 (1 mg/kg i.v.) or its vehicle (10% dimethyl sulfoxide) was given 45 min before the hemorrhage. Hemorrhage and resuscitation resulted in an increase in serum levels of (a) urea and creatinine and, hence renal dysfunction; alanine aminotransferase (ALT) and aspartate aminotransferase (AST) and, hence, hepatic injury. The potent PPAR-gamma agonist 15d-PGJ2 abolished the renal dysfunction and largely reduced the liver injury caused by hemorrhagic shock. In addition, 15d-PGJ2 also attenuated the lung and intestinal injury (determined by histology) caused by hemorrhage and resuscitation. The specific PPAR-gamma antagonist GW9662 reduced the protective effects afforded by 15d-PGJ2. 15d-PGJ2 did not affect the delayed fall in blood pressure caused by hemorrhage and resuscitation. The mechanisms of the protective effect of this cyclopentenone prostaglandin are, at least in part, PPAR-gamma dependent, as the protection afforded by 15d-PGJ2 was reduced by the PPAR-gamma antagonist GW9662. We propose that 15d-PGJ2 or other ligands for PPAR-gamma may be useful in the therapy of the organ injury associated with hemorrhagic shock.